Protein in Ovarian Cancers Deactivates Immune System Response

Cancer Network

By Leah Lawrence

Data from a new study has shown that ovarian cancer progression may be driven by the activation of an endoplasmic reticulum (ER) stress response factor called XBP1, which disrupts the function of dendritic cells and, subsequently, antitumor fighting T cells.
XBP1 is part of the ER stress response pathway—also called the unfolded protein response—that can allow tumors to grow and survive when they are deprived of nutrients and oxygen.

“Our findings suggest a strategy whereby a lethal cancer exploits the most conserved arm of the ER stress response in tumor-resident dendritic cells to disrupt their homeostasis, alter their local antigen-presenting capacity, and ultimately evade T cell-mediated immune control,” wrote study author Juan R. Cubillos-Ruiz, an instructor of immunology in medicine at Weill Cornell Medical College, and colleagues in the journal Cell.

imgres“While the ER stress response, and especially XBP1 activation, was previously shown to promote tumorigenesis, we now propose that this integrated cellular pathway further supports malignant progression by inhibiting the development of protective antitumor immunity via manipulation of normal dendritic cell function,” they wrote.

To make this discovery, Cubillos-Ruiz and colleagues examined the tumor microenvironment and found that ovarian cancer promoted the modification of proteins located in the ER, which, in turn, induced XBP1 activation and produced a buildup of lipid molecules within dendritic cells.

The researchers then tested whether or not XBP1 could be targeted. They injected mice with aggressive primary and metastatic ovarian cancer with nanoparticles, microscopic polymers that carried a genetic molecule that can silence the XPB1 gene. Dendritic cells detect the nanoparticles as invaders, and ingest them. Once inside, the nanoparticles delivered the molecule that turns XBP1 off, allowing dendritic cells to tell the immune system to attack the cancer.

“Activating T cell immunity to eliminate tumor cells is the most promising anticancer strategy since the development of chemotherapy, as demonstrated by the shrinkage of melanoma in response to checkpoint blockers,” the researchers wrote. “However, in most cases, the optimal cytotoxic activity of such tumor-reactive T cells is drastically reduced precisely because cancer-associated dendritic cells are unable to support T cell function.”

The results of this analysis show that deletion of XBP1 can transform tumor dendritic cells into ovarian cancer infiltrating T cells. If further developed, targeting XBP1 using nanotechnology-based system may help to slow or prevent the recurrence of ovarian cancers, the researchers wrote.

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